In two phase III studies, uric acid levels normalized for 20% to 48% of patients who had no other treatment options left (P=0.044 to P<0.001 versus placebo), reported John S. Sundy, M.D., Ph.D., of Duke in Durham, N.C., and colleagues at the American College of Rheumatology meeting here.

These improvements, which occurred rapidly, along with clinically significant reductions in urate deposits make the agent attractive, commented David A. Fox, M.D., of the University of Michigan in Ann Arbor, who is the ACR president.

However, safety findings from the tandem trials raised questions about long-tem use, said Dr. Fox, who was a moderator at the plenary session where the results were presented.

Most gout treatments work either by blocking uric acid production (xanthine oxidase inhibitors) or enhancing its excretion (uricosuric agents).

Pegloticase, though, breaks down uric acid with a recombinant form of the enzyme urate oxidase produced by most mammals.

"Humans are unique in getting gout," Dr. Fox said. "No animals below the level of primates get gout because they have this enzyme that breaks down uric acid."

Because humans don't make this enzyme, the body reacts to it as a foreign protein, he noted. "This is going to be a very difficult barrier to overcome when one talks about repeated long-term use."

In pooled results from the two identically designed studies by Dr. Sundy's group, adverse events leading to treatment discontinuation were more common with pegloticase (19% with every two-week dosing and 20% with every four-week dosing versus 2% with placebo, P<0.05).

Infusion reactions were one of the most common adverse events with the drug (26% every other week dosing and 41% with every four-week dosing versus 5% placebo, P<0.003). There was withdrawal from the study because of these reactions for 11% and 13% of patients, respectively.

Dr. Sundy noted that this likely reflected immunogenicity of the agent as 89% of pegloticase-treated patients tested positive for antibodies against it and the level of antibodies was correlated with infusion reaction incidence (P<0.001).

More concerning, though, were the eight serious cardiac adverse events with the investigational agent, including two sudden cardiac deaths, two exacerbations of congestive heart failure, two cases of dysrhythmia, one MI, and one case of angina.

There was one other death with pegloticase as well. There were no deaths or severe cardiac events the placebo group.

But, Dr. Fox cautioned, "We'll need to know for sure whether that has anything to do with the drug versus reflecting the underlying medical problems of these patients," he said.

Dr. Sundy agreed that given the small number of cardiovascular events, further data from longer follow-up in the extension phase are going to be needed to clarify whether the cardiovascular safety signal is real.

Savient Pharmaceuticals, which is developing pegloticase, has said it plans to file a biologics license application with the FDA this year with hopes of marketing the drug next year.

However, the FDA will likely want the safety concerns sorted out first, Dr. Fox said.

Furthermore, the agent is expensive and has to be given by intravenous infusion, he noted.

But for this group of patients with no other treatment options and severe disease, "pegloticase provides a favorable risk-benefit ratio for patients with treatment failure gout," Dr. Sundy said.

For the primary endpoint, more patients on pegloticase had plasma urate response with levels dropping below 6.0 mg/dL 80% of the time at three and six months.

In the intent-to-treat analysis of the two studies, none of the placebo group patients responded. But 47% and 38% of patients given pegloticase every other week were responders (both P<0.001) as well as 20% and 48% of those given the agent every four weeks (P=0.044 and P<0.001).

The two studies randomized a total of 225 patients to six months of double-blind treatment with placebo, 8 mg IV pegloticase every other week, or 8 mg every four weeks followed by open-label extension for another 12 months.

All patients were considered treatment failures with at least three flares of gout in the prior 18 months or at least one tophus or gouty arthropathy and failure of the maximum medically-appropriate dose of allopurinol (Aloprim, Zyloprim) or contraindication to allopurinol.

Among the significant secondary efficacy findings, the researchers reported for the two dose groups compared with placebo:

More frequent complete resolution of at least one tophus without new tophi (40.4%, 21.2%, and 3.7%)

Higher quality of life on physical and arthritis-specific subscales

Greater reduction in number of tender joints at six months

Fewer gout flares with continued improvement over 18 months

Rapid reduction in uric acid levels sustained over follow-up

Dr. Sundy said it's not clear yet how long dosing would need to continue to maintain the effects seen in the trial but noted that retreatment protocols are now underway.

The study was sponsored by Savient Pharmaceuticals.

Dr. Sundy and co-authors reported conflicts of interest for Savient Pharmaceuticals. Duke University and one co-author reported holding patent rights in pegylated urate oxidase and its use.

Dr. Fox reported no conflicts of interest.

Reviewed by Zalman S. Agus, MD Emeritus Professor University of Pennsylvania School of Medicine

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